Risk factors for non-specific low back pain in older people: a systematic review with meta-analysis.

PURPOSE: To conduct a systematic review about risk factors associated with non-specific low back pain (LBP) in older people. METHODS: The study protocol was prospectively registered with Prospero (CRD42020191619). This systematic review with meta-analysis included cohort studies that investigated risk factors for LBP in older people. The following databases were searched up to 12 December 2020: MEDLINE (Ovid), Embase, CINAHL, SCOPUS and Web of Science. Two independent reviewers appraised methodological quality using the Critical Appraisal Checklist for Cohort Studies instrument. RESULTS: We identified 3939 potentially relevant publications. After removing duplicates, screening title, and abstracts, we assessed 86 publications in full text. We included the remaining 11 publications for analysis. There is strong evidence that depressive symptoms are a risk of reporting future back pain onset (I2 = 52,7%, Odds ratio 1.4, CI 1.28-1.53). CONCLUSION: Depressive symptoms are a risk factor for LBP in older people. Due to the limitations of the literature, the role of some risk factors remains unclear. An additional high-quality prospective cohort is needed to better elucidate these relationships.

Urinary symptoms in older people with low back pain: Prevalence, clinical, and functional factors associated.

AIMS: To identify the prevalence, clinical and functional factors associated with urinary symptoms (US) in community-dwelling older adults with acute low back pain (LBP). METHODS: This was a cross-sectional study of data's baseline of Back Complaints in the Elders Consortium. All elders had LPB heightened. We analyzed data on urinary symptoms, intensity of pain (Numerical Rating Scale (NRS), disability (Roland Morris [RM]), depressive symptoms (CES-D), and gait speed (m/s) in the Brazilian older adults. The sample was of 586 consecutive participants of BACE-Study. Ethical approval was obtained. In addition to the prevalence analysis, logistic regression analysis was performed. RESULTS: The prevalence of US was 18.4% and were associated with CES-D (odds ratio [OR] = 2.84; 95% confidence interval [CI] 1.66-4.86), slower gait speed (OR = 0.33; 95% CI 0.14-0.78), and LBP-related disability (OR = 1.09; 95% CI 1.04-1.13) after adjusting for radiculophaty and other confounding factors. CONCLUSIONS: In community-dwelling older people with LBP, US were associated with depressive symptoms, gait speed, and disability. Our findings may provide a new framework for US management with respect to clinical and functional capacity. Specific physical examinations should be encouraged to assess the with acute LBP and US. Others factors can be associated with US in elders with LBP.

Evaluating the Antifungal Activity of α-Bisabolol in Association with NaCl on Fusarium oxysporum in Maize Grains.

Fusarium infections result in reduced maize grain (Zea mays L.) yields and notable impacts on human and animal health. Research involving natural products to control fungi in food is a promising alternative. Combinations of α-bisabolol (AB) and sodium chloride (NaCl) may suggest the use of lower effective concentrations of the drugs. This study aimed to evaluate the antifungal potential of AB associated with NaCl against Fusarium oxysporum strains isolated from maize. Minimum inhibitory concentrations (MICs) values of AB and NaCl were determined by microdilution, and an association study was performed (checkerboard). Effects on fungal mycelial growth (poisoned substrate technique) and a maize grain contamination model were analyzed. AB presented MIC values ranging from 128 and 1024 µg/mL; NaCl inhibited fungal growth at 16,384 µg/mL. The AB/NaCl association study revealed synergism by decreasing inhibitory concentrations by eight times. In corn kernels, AB and NaCl, whether isolated (at MIC) or in association (at sub-inhibitory concentrations), significantly inhibited in vitro mycelial growth (P < 0.05). Further analysis of liquid from a canned maize sample also revealed the fungistatic effects of the compounds associations (P < 0.05). The results confirm the antifungal potential of AB, whether isolated or in association with NaCl to control F. oxysporum in maize.

Nanoparticle mucoadhesive system as a new tool for fish immune system modulation.

Recently, chitosan-based nanoparticles with mucoadhesive properties emerged as a strategy for mucosal drug release. This study aimed to characterize the interaction of mucoadhesive system chitosancoated PLGA nanoparticles (NPMA) with fish external mucus. NP suspensions with fluorescent probe were prepared and characterized by size, polydispersity, zeta potential and pH measures. In post-exposure fish were observed an increase in fluorescence imaging over time and it was significantly influenced by NPMA concentration. We also observed the main predominance the fluorescence in the spleen, followed by liver, gill and other tissues. The use of mucoadhesive nanocarriers becomes an alternative for administration of drugs and immunomodulators in immersion systems since the nanosystem can adhere to the mucosal surface of the fish with little residual effect in the water.

Prevalence of Candida tropicalis and Candida krusei in onychomycosis in João Pessoa, Paraiba, Brazil from 1999 to 2010.

Over time, as the etiology of onychomycosis has developed, yeasts from the genus Candida have emerged as important etiological agents. This study aimed to determine the frequency of yeast caused onychomycosis in Joao Pessoa, Paraíba, Brazil from 1999 to 2010. A retrospective study from January 1999 to December 2010 evaluated the results of onychomycosis positive direct mycological exams (DME) - for yeast and realized in the Hemato(r) Clinical Laboratory. Women were the most affected by onychomycosis which occur preferentially in adults, and the toenails are the favorite yeast targets. The prevalent yeasts were Candida tropicalis and C. krusei.

Plasma proteome responses in zebrafish following λ-carrageenan-Induced inflammation are mediated by PMN leukocytes and correlate highly with their human counterparts.

Regulation of inflammation is a critical process for maintaining physiological homeostasis. The λ-carrageenan (λ-CGN) is a mucopolysaccharide extracted from the cell wall of red algae (Chondrus crispus) capable of inducing acute intestinal inflammation, which is translated into the production of acute phase reactants secreted into the blood circulation. However, the associated mechanisms in vertebrates are not well understood. Here, we investigated the crucial factors behind the inflammatory milieu of λ-CGN-mediated inflammation administered at 0, 1.75, and 3.5% (v/w) by i.p. injection into the peritoneal cavity of adult zebrafish (ZF) (Danio rerio). We found that polymorphonuclear leukocytes (neutrophils) and lymphocytes infiltrating the ZF peritoneal cavity had short-term persistence. Nevertheless, they generate a strong pattern of inflammation that affects systemically and is enough to produce edema in the cavity. Consistent with these findings, cell infiltration, which causes notable tissue changes, resulted in the overexpression of several acute inflammatory markers at the protein level. Using reversed-phase high-performance liquid chromatography followed by a hybrid linear ion-trap mass spectrometry shotgun proteomic approach, we identified 2938 plasma proteins among the animals injected with PBS and 3.5% λ-CGN. First, the bioinformatic analysis revealed the composition of the plasma proteome. Interestingly, 72 commonly expressed proteins were recorded among the treated and control groups, but, surprisingly, 2830 novel proteins were differentially expressed exclusively in the λ-CGN-induced group. Furthermore, from the commonly expressed proteins, compared to the control group 62 proteins got a significant (p < 0.05) upregulation in the λ-CGN-treated group, while the remaining ten proteins were downregulated. Next, we obtained the major protein-protein interaction networks between hub protein clusters in the blood plasma of the λ-CGN induced group. Moreover, to understand the molecular underpinnings of these effects based on the unveiled protein sets, we performed a bioinformatic structural similarity analysis and generated overlapping 3D reconstructions between ZF and humans during acute inflammation. Biological pathway analysis pointed to the activation and abundance of diverse classical immune and acute phase reactants, several catalytic enzymes, and varied proteins supporting the immune response. Together, this information can be used for testing and finding novel pharmacological targets to treat human intestinal inflammatory diseases.

Chronic apnea during REM sleep increases arterial pressure and sympathetic modulation in rats.

STUDY OBJECTIVES: Obstructive sleep apnea can induce hypertension. Apneas in REM may be particularly problematic: they are independently associated with hypertension. We examined the role of sleep stage and awakening on acute cardiovascular responses to apnea. In addition, we measured cardiovascular and sympathetic changes induced by chronic sleep apnea in REM sleep. METHODS: We used rats with tracheal balloons and electroencephalogram and electromyogram electrodes to induce obstructive apnea during wakefulness and sleep. We measured the electrocardiogram and arterial pressure by telemetry and breathing effort with a thoracic balloon. RESULTS: Apneas induced during wakefulness caused a pressor response, intense bradycardia, and breathing effort. On termination of apnea, arterial pressure, heart rate, and breathing effort returned to basal levels within 10 s. Responses to apnea were strongly blunted when apneas were made in sleep. Post-apnea changes were also blunted when rats did not awake from apnea. Chronic sleep apnea (15 days of apnea during REM sleep, 8 h/day, 13.8 ± 2 apneas/h, average duration 12 ± 0.7 s) reduced sleep time, increased awake arterial pressure from 111 ± 6 to 118 ± 5 mmHg (p < 0.05) and increased a marker for sympathetic activity. Chronic apnea failed to change spontaneous baroreceptor sensitivity. CONCLUSION: Our results suggest that sleep blunts the diving-like response induced by apnea and that acute post-apnea changes depend on awakening. In addition, our data confirm that 2 weeks of apnea during REM causes sleep disruption and increases blood pressure and sympathetic activity.

Anti-inflammatory effect of rosmarinic acid isolated from Blechnum brasiliense in adult zebrafish brain.

Neuroinflammation has been associated to neurodegenerative disease development, with evidence suggesting that high levels of proinflammatory cytokines promote neuronal dysfunction and death. Therefore, it is necessary to study new compounds that may be used as adjuvant treatments of neurodegenerative diseases by attenuating the inflammatory response in the central nervous system (CNS). The aim of this study was to utilize the lipopolysaccharide (LPS) induction model of neuroinflammation to evaluate the modulation of inflammation by rosmarinic acid (RA) isolated from Blechnum brasiliense in adult zebrafish. First, we investigated the toxicity and antioxidant properties of fractionated B. brasiliense extract (ethyl acetate fraction- EAF) and the isolated RA in zebrafish embryos. Next, we developed a model of neuroinflammation induction by intraperitoneal (i.p.) injection of LPS to observe the RA modulation of proinflammatory cytokines. The median lethal concentration (LC50) calculated was 185.2 ± 1.24 µg/mL for the ethyl acetate fraction (EAF) and 296.0 ± 1.27 µM for RA. The EAF showed free radical inhibition ranging from 23.09% to 63.44% at concentrations of 10-250 µg/mL. The RA presented a concentration-dependent response ranging from 18.24% to 47.63% at 10-250 µM. Furthermore, the RA reduced LPS induction of TNF-α and IL-1ß levels, with the greatest effect observed 6 h after LPS administration. Thus, the data suggested an anti-inflammatory effect of RA isolated from B. brasiliense and reinforced the utility of the new model of neuroinflammation to test the possible neuroprotective effects of novel drugs or compounds.

Zebrafish as a model to study inflammation: A tool for drug discovery.

This study aims to demonstrate the applicability and importance of zebrafish (Danio rerio) model to study acute and chronic inflammatory responses induced by different stimuli: carrageenan phlogogen (nonimmune); acute infection by bacteria (immune); foreign body reaction (chronic inflammation by round glass coverslip implantation); reaction induced by xenotransplantation. In addition to the advantages of presenting low breeding cost, high prolificity, transparent embryos, high number of individuals belonging to the same spawning and high genetic similarity that favor translational responses to vertebrate organisms like humans, zebrafish proved to be an excellent tool, allowing the evaluation of edema formation, accumulation of inflammatory cells in the exudate, mediators, signaling pathways, gene expression and production of specific proteins. Our studies demonstrated the versatility of fish models to investigate the inflammatory response and its pathophysiology, essential for the successful development of studies to discover innovative pharmacological strategies.

Mycoplasma pulmonis and lymphoma in bioassays in rats.

Lymphomas were reported to be induced in rats in bioassays of aspartame, methyl-tertiary-butyl ether (MTBE), and other chemicals conducted by a nonprofit cancer research organization. European regulatory authorities concluded that lymphomas in the aspartame study were caused by Mycoplasma pulmonis and suggested that this also was the case for the MTBE bioassay. To assess the role of M. pulmonis in these bioassays, we reviewed the tumor data for the aspartame and MTBE bioassays and, additionally, the organization's bioassay of methanol. For all 3 studies, the most frequently reported hematopoietic neoplasm was lympho-immunoblastic lymphoma, the most frequently affected organ was the lung, and, in almost half of the rats with this diagnosis, the lung was the only affected organ. Lesions diagnosed as lymphoma in published illustrations had pleomorphic cellular morphology and appeared to contain neutrophils. Information from these reports and other sources indicated that lesions typical of M. pulmonis disease were prevalent among the aspartame and MTBE study rats and that the rats were not specific-pathogen-free. Because the lymphoma type, cellular morphology, and organ distribution reported in these studies are atypical of lymphoma in rats, because lymphocyte and plasma cell accumulation in the lung is characteristic of M. pulmonis disease, and because M. pulmonis disease can be exacerbated by experimental manipulations, including chemical treatment, we suggest that a plausible alternative explanation for the reported results of these bioassays is that the studies were confounded by M. pulmonis disease and that lesions of the disease were interpreted as lymphoma.

[Corrigendum] Daily or weekly dosing with EGFR inhibitors, gefitinib and lapatinib, and AKT inhibitor MK2206 in mammary cancer models.

The AKT inhibitor employed in this article was identified as MK 2206 (8­[4­(1­aminocyclobutyl) phenyl]­9­phenyl­1,2,4­ triazolo[3,4­f][1,6]naphthyridin­3(2H)­one hydrochloride (1:2). However, another AKT inhibitor was actually used, which is typically identified as Akt I­1,2 (HC,I. IPA (2­[4­(3­phenylquinoxalin­2­yl)phenyl]propan­2­amine hydrochloride isopropanol (1:1:1). Therefore, all references to MK 2206 in the paper should have been made to Akt I­1.2. Based on the experience of the present authors with a range of targeted inhibitors, it is expected that both inhibitors would have given rise to similar results; therefore, the results obtained in the paper are not likely to have been greatly affected as a consequence of the use of the alternative inhibitor. The authors regret that this error was not identified sooner, prior to the publication of the article, and regret any inconvenience that has been caused. [the original article was published in Oncology Reports 40: 1545­1553, 2018; DOI: 110.3892/or.2018.6313].

Acute-phase proteins during inflammatory reaction by bacterial infection: Fish-model.

Acute-phase protein (APPs) serum levels have been studied in many human diseases, and their components contribute to host defense during the evolution of infectious diseases by acting as part of the innate immune system. Based on the importance of establishing new experimental models, the present investigation evaluated the modulation of APPs following inflammatory stimulus by the inoculation of Aeromonas hydrophila in tilapias. Fish were sampled 6 and 24 hours post-infection. Tilapias presented increase of positive APPs such as ceruloplasmin, haptoglobin, alpha-2-macroglobulin and complement C3, as well as decrease of negative APPs such as albumin and transferrin. The protein response of tilapias during the course of bacterial infection showed correlation with the kinetics of cellular accumulation in the inflamed focus with significant increase of granulocytes, thrombocytes, lymphocytes and macrophages. However, granulocytes were the predominant cells, associated with increment in the reactive oxygen species (ROS) production. Showing responses similar to those observed in humans, the modulation of APPs and the kinetics of cellular accumulation in the exudate demonstrate the feasibility of this alternative experimental model for advances and studies to understand changes in pathophysiological mechanisms of acute inflammatory reaction due to bacterial infection.

Daily or weekly dosing with EGFR inhibitors, gefitinib and lapatinib, and AKt inhibitor MK2206 in mammary cancer models.

Daily vs. weekly dosing with EGFR inhibitors (gefitinib and lapatinib) and an AKT inhibitor (MK2206) were compared in two rodent breast cancer models. Female Sprague-Dawley rats were administered methylnitrosourea (MNU) at 50 days of age, and gefitinib (daily/weekly dosing at 10/70 mg/kg BW) or lapatinib (daily/weekly dosing at 75/525 mg/kg BW) were administered by gavage beginning 5 days after MNU. For the prevention studies, weekly or daily dosing with gefitinib or lapatinib reduced cancer multiplicity >75%, and all treatments reduced tumor weights by >90%. For the therapeutic studies, MNU-treated rats were followed until small palpable mammary cancers developed. The rats were then treated daily or weekly as above for 6 weeks. Either daily or weekly dosing with lapatinib or gefitinib caused regression in >50% of the tumors. Immunohistochemistry biomarker studies in palpable mammary cancers following a weekly dose of gefitinib showed that 1 day (but not 7 days) after treatment, the levels of phosphorylated EGFR1 were significantly decreased. In an ER-negative (ER-) Neu-overexpressing model employing MMTV-Neu/P53KO mice, daily (100 mg/kg BW/day, 5 days each week), or weekly dosing (500 or 250 mg/kg BW) with gefitinib reduced tumor multiplicity 65, 85 and 75%, respectively. In the MNU prevention model, daily dosing (100 mg/kg BW/day) with the allosteric AKT inhibitor MK2206 was ineffective, while weekly dosing (700 mg/kg BW) reduced the final tumor weight >70%. Combining weekly MK2206 with the aromatase inhibitor vorozole (0.12 mg/kg BW/day) showed that each compound alone reduced tumor multiplicity 40-50%. The combination reduced cancer multiplicity ~70%. These studies demonstrate the efficacy of weekly dosing with various protein kinase inhibitors; raising the possibility of employing these agents in a breast cancer preventive setting.

Effects of folate deficiency and supplementation on methylnitrosourea-induced rat mammary tumors.

BACKGROUND: There are metabolic and epidemiologic data consistent with the hypothesis that folate deficiency increases the likelihood of cancer. Conversely, it is also known that folate is necessary for cancer growth, but few experiments in laboratory animals have evaluated the effects of folate deficiency on the development of chemically induced cancers. PURPOSE: Our purpose was to determine the effects of nutritional folate deficiency in female Fischer 344 rats on initiation and early promotion of methylnitrosourea (MNU)-induced mammary cancer. METHODS: Rats (age, 27 days) were fed a folic acid-deficient diet (AIN-76A) supplemented with glycine and succinylsulfathiazole [FA(0)]; the FA(0) diet supplemented with 2 or 40 mg of folic acid per kilogram [FA(2) or FA(40), respectively]; or the FA(0) diet supplemented with 20 mg of folinic acid per kilogram [FL(20)]. At 57 days of age, each diet-treated group (30 rats in each group) received MNU (50 mg/kg) by intravenous injection. Immediately after MNU treatment, all animals were fed the AIN-76A complete diet containing 2 mg of folic acid per kilogram. Control groups were fed the AIN-76A complete diet throughout the entire experiment. RESULTS: After 4 weeks, folate deficiency, but not anemia or growth suppression, was documented by lower folate levels in plasma and red blood cells in the group receiving the FA(0) diet. Cancer multiplicity (i.e., number of mammary cancers per number of tumor-bearing animals) at 180 days after MNU injection was 1.32, 1.90, 2.14, and 2.73 mammary cancers per tumor-bearing animal in the FA(0), FA(2), FA(40), and FL(20) groups, respectively; the value in the FA(0) group was statistically significant compared with the values in the other groups. The time required for 50% of the rats to develop palpable mammary cancer was 170, 142, 100, and 85 days, respectively. The value of 170 days for the FA(0) group was statistically significant compared with the values of 100 and 85 days. Mammary cancer incidence was 63%, 70%, 72%, and 73%, respectively; these percentages were not significantly different. CONCLUSIONS: Folate deficiency suppresses and folate supplementation enhances initiation or early promotion of MNU-induced mammary cancer in rats, even when the folate-deficient rats do not have anemia or growth suppression. IMPLICATION: Since the rat is relatively resistant to folate deficiency anemia, other animal models should be used to test the effect of folate nutriture on carcinogenesis.

What the Erythrocytic Nuclear Alteration Frequencies Could Tell Us about Genotoxicity and Macrophage Iron Storage?

Erythrocytic nuclear alterations have been considered as an indicative of organism's exposure to genotoxic agents. Due to their close relationship among their frequencies and DNA damages, they are considered excellent markers of exposure in eukaryotes. However, poor data has been found in literature concerning their genesis, differential occurrence and their life span. In this study, we use markers of cell viability; genotoxicity and cellular turn over in order to shed light to these events. Tilapia and their blood were exposed to cadmium in acute exposure and in vitro assays. They were analyzed using flow cytometry for oxidative stress and membrane disruption, optical microscopy for erythrocytic nuclear alteration, graphite furnace atomic absorption spectrometry for cadmium content in aquaria water, blood and cytochemical and analytical electron microscopy techniques for the hemocateretic aspects. The results showed a close relationship among the total nuclear alterations and cadmium content in the total blood and melanomacrophage centres area, mismatching reactive oxygen species and membrane damages. Moreover, nuclear alterations frequencies (vacuolated, condensed and blebbed) showed to be associated to cadmium exposure whereas others (lobed and bud) were associated to depuration period. Decrease on nuclear alterations frequencies was also associated with hemosiderin increase inside spleen and head kidney macrophages mainly during depurative processes. These data disclosure in temporal fashion the main processes that drive the nuclear alterations frequencies and their relationship with some cellular and systemic biomarkers.

Acute-phase proteins during inflammatory reaction by bacterial infection: fish-model

Acute-phase protein (APPs) serum levels have been studied in many human diseases, and their components contribute to host defense during the evolution of infectious diseases by acting as part of the innate immune system. Based on the importance of establishing new experimental models, the present investigation evaluated the modulation of APPs following inflammatory stimulus by the inoculation of Aeromonas hydrophila in tilapias. Fish were sampled 6 and 24 hours post-infection. Tilapias presented increase of positive APPs such as ceruloplasmin, haptoglobin, alpha-2-macroglobulin and complement C3, as well as decrease of negative APPs such as albumin and transferrin. The protein response of tilapias during the course of bacterial infection showed correlation with the kinetics of cellular accumulation in the inflamed focus with significant increase of granulocytes, thrombocytes, lymphocytes and macrophages. However, granulocytes were the predominant cells, associated with increment in the reactive oxygen species (ROS) production. Showing responses similar to those observed in humans, the modulation of APPs and the kinetics of cellular accumulation in the exudate demonstrate the feasibility of this alternative experimental model for advances and studies to understand changes in pathophysiological mechanisms of acute inflammatory reaction due to bacterial infection.

Anhydroretinol, a retinoid active in preventing mammary cancer induced in rats by N-methyl-N-nitrosourea.

As determined by in vitro tests, anhydroretinol, a metabolic product of retinol, was bound specifically by serum retinol-binding protein and by cellular retinol-binding protein but not by cellular retinoic acid-binding protein or the nuclear receptors, RARs and RXRs. For rats dosed with the mammary carcinogen, N-methyl-N-nitrosourea (45 mg/kg body weight) and given diets containing either the retinoid vehicle, anhydroretinol (67, 134, 268, or 536 mg/kg of diet), or retinyl acetate (328 mg/kg of diet), there were, over a 90-day observation period, no significant differences in body weights. The compound did not accumulate in liver tissue or cause an increase in hepatic levels of retinyl palmitate (potential problems observed with other retinoids). The numbers of mammary cancers were as follows: no retinoid, 4.5/rat; retinyl acetate, 2.1/rat; and increasing doses of anhydroretinol, 2.9, 3.3, 3.0, and 1.7/rat, respectively. Thus, anhydroretinol, at non-toxic levels, was effective as a preventive agent in this experimental model of breast cancer.

Effects of acute and chronic body weight gain reductions in the evaluation of agents for efficacy in mammary cancer prevention.

Studies were performed to determine the effects of moderate decreases in body weight gain on mammary carcinogenesis. The levels of depressions in weight gain were those often observed in the evaluation of chemopreventive agents. In the first experiment, the effects of acute and chronic reductions of body weight gain when started after carcinogen treatment were examined in young rats (MNU at 50 days of age). Significant decreases (36%) in mammary cancers occurred in groups of rats that underwent a 12% acute reduction in body weight gain as compared with ad libitum controls. In contrast, chronic weight reductions of up to 12% had minimal effects on cancer multiplicities, while a 15% chronic reduction significantly decreased cancer numbers (26%). A second experiment evaluated the efficacy of toremifene (7.0 mg/kg diet), an estrogen/anti-estrogen, and the effect of toremifene-matched body weight gain reduction that occurred during the study. Toremifene caused a chronic reduction in body weight that resulted in a 10% decrease in final body weight at the end of the study. While toremifene-treated rats exhibited a 67% decrease in the number of mammary cancers, the rats which similarly exhibited a 10% decrease in final body weight showed only a 14% decrease in cancer number. Thus, the weight effects observed with toremifene, similar estrogens/anti-estrogens, and other classes of chemopreventive compounds (where chronic body weight reductions are 10% or less) imply that the body weight reduction has a limited effect on overall chemopreventive activity. A third study examined the effect of chronic body weight gain reduction on mammary cancers induced in older rats (MNU given at 100 days of age). This model more closely resembles the status of the breast tissue of mature women currently enrolled in clinical trials of chemopreventive agents. Under these conditions chronic reductions in body weight up to 15% had minimal effects on mammary carcinogenesis. These data further demonstrated that acute body weight reductions in young rats at the time of carcinogen treatment can be a concern in interpretation of the chemopreventive activity of an agent, but that moderate chronic depressions of body weight gain probably do not play a significant role.

Short-term hormone treatment as a chemopreventive method against mammary cancer initiation in rats.

Because previous data had suggested that short-term treatment with pharmacological doses of estradiol and progesterone might be an effective means of preventing mammary cancer initiation, additional experiments were performed to confirm this observation and to determine if lower doses of the hormones would also have chemopreventive activity. Rats treated with the steroids for five weeks and administered the carcinogen (methylnitrosourea) three weeks later were observed for one year for the appearance of mammary cancers. Hormone pretreated rats exhibited a reduction in number of mammary cancers of approximately 90% from rats receiving the steroid vehicle. During the extended observation period, treatment with steroids did not induce gross or histological lesions in any tissues. In a separate experiment, decreasing the dose levels from 20 micrograms estradiol plus 4 mg progesterone to 5 mg estradiol plus 2 mg progesterone did not significantly alter the chemopreventive efficacy of the treatment regimen. Differentiation of the mammary gland to a secretory state with hormones apparently alters the epithelial cells so that, even after involution has occurred, the gland maintains its resistance to a carcinogenic insult.

Effect of retinyl acetate and 4-hydroxyphenylretinamide on initiation of chemically-induced mammary tumors.

The anti-promotional effect of retinoids on chemically-induced mammary carcinogenesis in the rat is well established. The present studies were performed to determine the effect of long-term feeding of retinyl acetate and 4-hydroxyphenylretinamide (4-HPR) on initiation of mammary tumors induced by MNU or DMBA. Retinyl acetate (328 mg/kg of diet) or 4-HPR (782 mg/kg of diet) was added to the diet of female Sprague-Dawley rats for two months prior to the administration of the carcinogens. In the MNU model, a 50% increase in the number of mammary adenocarcinomas was observed in rats pretreated with retinyl acetate, while pretreatment with 4-HPR resulted in a 93% increase in the number of cancers. Continued treatment with 4-HPR throughout the study, however, caused a reduction in cancer number. In the DMBA mode, pretreatment with these retinoids significantly increased the number of benign mammary tumors, but not mammary cancers. These data suggest that newly synthesized retinoids should be evaluated for chemopreventive activity against mammary cancer initiation as well as for their anti promotional activity.